Method for controlling the growth of fungi and plants



United States Patent Ofi ice 3,297,424 Patented Jan. 10, 1967 Thisinvention relates to novel amine derivatives of o-benzyl-p-chlorophenoland the acid salts thereof. More particularly, this invention isconcerned with the condensation products of a selected heterocyclicsecondary amine, formaldehyde, and o-benzyl-p-chlorophenol. Suchproducts are found to possess useful and unexpected pesticidal activity,particularly as herbicides and fungicities.

The following equation is representative for preparing the compounds ofthe present invention:

The present application is a division of United States Serial No.225,367, filed September 21, 1962, now US. Patent No. 3,255,194, grantedJune 7, 1966.

The term pesticide, as used herein, connotes compounds useful as activeingredients in biological toxicants such as one or more of thefollowing: bactericide, fungicide, insecticide, nematocide, andherbicide.

It is an object of this invention to provide new amine derivatives ofo-benzyl-p-chlorophenol and the acid salts thereof.

A further object of this invention is to incorporate said derivatives informulations which display pesticidal activity, particularly asherbicides and fungicides.

The novel compounds of this invention have the general formula,

where R is selected from the group consisting of methyl and ethyl, b isan integer from 0 to 2, X is selected from the group consisting ofoxygen, NCH CH and a is an integer from O to 1.

This class of compounds can be prepared by the condensation reaction ofa selected heterocyclic secondary amine with formaldehyde, or aformaldehyde-yielding substance, and o-benzyl-p-chlorophenol. Thereaction of an amine, formaldehyde, and a phenol is known as theMannich-type reaction. The details of the Mannich reaction have been setforth in many texts, one of which is Organic Reactions, volume I, pages303 et seq., b Adams, Bachman, Fieser, Johnson and Snyder. Briefly, theMannich reaction involves the condensation of ammonia, or a primary or asecondary amine, with formaldehyde and a compound containing at leastone reactive hydrogen. In the present invention, the compound having thereactive hydrogen is a substituted phenol, o-benzyl-pchlorophenol.

01 where represents a heterocyclic secondary amine having each of the Nring bonds attached to a carbon atom.

As illustrative of the heterocyclic secondary amines, but not limitativethereof, are: morpholine, 2-methyl-5- ethylmorpholine,2,3-dimethylmorpholine, piperidine, 2- methylpiperidine,4-ethylpiperidine, 3 ethylpiperidine, piperazine, 2 ethylpiperazine, 3methylpiperazine, N- methylpiperazine, 2,3 diethylpiperazine,pyrrolidine, 2- methylpyrrolidine, 3-ethylpyrrolidine, 2-ethyl-4methylpyrrolidine, 3,4-dimethylpyrrolidine, and the like. The mono anddihydrochloride salts of the compounds prepared with these amines arealso useful as described above.

In performing the Mannich condensation, the formaldehyde may be added asan aqueous solution or as paraformaldehyde. When aqueous formaldehyde isutilized, the condensation is ordinarily carried out by stirring in anaqueous medium. If paraformaldehyde is utilized, an inert solvent ispreferred. The inert solvent selected should not be capable ofundergoing the Mannich condensation unless it is one of the reactants,in which case an excess thereof may be used. Examples of some of theinert solvents which do not undergo the Mannich condensation areethanol, isopropyl alcohol, isoamyl alcohol, benzene, toluene, xylene,and the like.

In the preparation of the compounds of this invention, it is preferredto employ an excess of formaldehyde and the heterocyclic secondaryamine. An excess of formaldehyde and the secondary amine ranging from1.005 to 1.15 molar equivalents (preferably about 1.1 molar equivalents)provides excellent yields.

The nature of this invention will be more fully understood by referenceto the following examples, which are set forth herein solely for thepurpose of illustration and are not to be construed as limiting thescope of the present invention.

EXAMPLE I 2-berzzyl-4-chl0r0-6-pyrrolidinylmethylphenol To a suitablereactor there are added 43.8 grams (0.2 mol.) ofo-benzyl-p-chlorophenol, 6.6 grams (0.22 mol.) of paraformaldehyde, 15.6grams (0.22 mol.) of pyrrolidine, and 75 ml. of absolute ethyl alcohol.The reaction mixture is heated to gentle reflux and held there for 18hours. The reaction mixture, while hot, is poured over ice, causing afraction of the reaction mixture to solidify. The bulk of the Water isdecanted, and the remaining solid fraction is dissolved in hot absoluteethyl alcohol. Upon cooling, the dissolved solid crystallizes. Thecrystals are separated by filtration and air dried, yielding 47 grams of2-benzyl-4-chloro-6-pyrrolidinylmet-hylphenol as crystalline needles,M.P. 6869 C. Recrystallization from absolute ethyl alcohol does notchange the melting point. Analysis shows 4.6% nitrogen against 4.6%calculated for CmHg CINO. I

Five grams of the free 'base are dissolved in ether, and dry hydrogenchloride gas is sparged therein until the solution is acidic. A whiteprecipitate forms and is separated by filtration. The precipitate isWashed Well with ether and air dried, yielding 5.7 grams of thehydrochloride salt. A first recrystallization from ethyl acetateproduces crystal platelets, M.P. 189.5190.5 C. A secondrecrystallization from ethyl acetate, with a filtering step from hotethyl acetate, also yields crystalline platelets, M.P. 190-191 C.Analysis shows 10.6% ionic 2-benzyl-4-chlor0-6-(4-methyl-piperazinylmethyl phenol dihydrochloride CH GHZ @on onz-N NCH3nol ong-oflnoi To a suitable reactor there are added 21.9 grams (0.1mol.) of o-benzyl-p-chlorophenol, 3.3 grams (0.11 mol.) ofparafonnaldehyde, 11.0 grams (0.11 mol.) of N- methyl piperazine, and 50ml. of absolute ethyl alcohol. The mixture is heated gently to refluxtemperature and held there for 18 hours. The mixture is then poured overice, and a fraction thereof forms a viscous oil. The oil is separatedfrom the Water by decantation and dried. The oil is then dissolved inethanol, and hydrogen chloride gas is passed into the solution untilacidic. Ether is then added to the solution until the cloudy point isreached, at which time the cloudy solution is .gently heated on a steambath. A precipitate forms. The reaction mixture is cooled in an icebath, and thereafter the solid is removed by filtering and air dried. Ayield of 7.0 grams of 2benzyl-4-chloro-6-(4-methylpiperazinylmethyl)phenol dihydrochloride,M.P. 227-231 C., is obtained. The solid is purified by refluxing with200 ml. of ethyl acetate, and separated therefrom by filtration,yielding a purified product showing an M.P. 231-232 C.

EXAMPLE III 2-belzzyl-4-chl0r0-6-piperidinylmethylphenol To a suitablereactor there are added 43.8 grams (0.2 mol.) ofo-benzyl-p-chlorophenol, 6.6 grams (0.22 mol.) of paraformaldehyde, 18.7grams (0.22 mol.) of piperidine, and 100 ml. of absolute ethyl alcohol.The reaction mixture is heated to gentle reflux and held there for 18hours.

The reaction mixture, while hot, is poured over 400 grams of ice,causing a fraction of the reaction mixture to solidify. The solidfraction is removed by filtration, washed with water, and thereafterdissolved in hot absolute ethanol. The solution is allowed to cool andstand at room temperature. There is formed 9.0 grams of2-benzyl-4-chloro-6-piperidinylmethylphenol as a dark, oily substancewhich solidifies upon further cooling and is separated by decanting theethyl alcohol. The decanted solution is further cooled on an ice bath. Asolid precipitate forms, light tan in color, and is removed byfiltration and air dried, yielding 44.0 grams of 2-benzyl-4-chloro-6-piperidinylmethylphenol, M.P. 83-84 C. The total yieldis 53.0 grams of 2-'benzyl-4-chloro-6- piperidinylmethylphenol, or 85%theoretical.

Following the procedure as outlined in Examples I- HI, othero-benzyl-p-chlorophenol condensation products and their acid salts arereadily prepared. Such other representative derivatives include:

2 benzyl 4 chloro-6-(Z-methyl-S-ethyl-morpholinomethyl) phenol,

2 benzyl-4-chloro-6-(2,3-dimethylmorpholinomethyl) phenol hydrochloride,

2 benzyl 4-chloro-6-(4-ethyl-piperidinylmethyl)phenol,

2 benzyl 4 chloro 6-(3-methyl-piperazinylmethyl) phenol,

2 benzyl 4-chloro-6-(2,3-diethyl-piperazinylmethyl) phenol,

2 benzyl-4-chloro-6-(3-ethyl-pyrrolidinylmethyl)phenol,

2 benzyl-4-chloro-6-(3,4-dimethyl-pyrrolidinylmethyl)phenol,

2 benzyl 4 chloro-6-(2-ethyl-4-methyl-pyrrolidinylmethyl) phenol, andthe like.

It has been found that the 2-benzyl-4-chloro-6-heterocyclicaminomethylphenols and their acid salts exhibit pesticidal activity, particularlyas herbicides and fungicides. The activity of said compounds isdetermined according to the following procedures:

H erbicides pre-emergent Aluminum pans are filled level with a goodgrade of top soil which has been screened through A wire mesh. The soilsurface is then compacted to a depth of from the top of the pan. Apredetermined number of seeds of each of morning glory, wild oats, bromegrass, rye grass, buckwheat, radish, sugar beet, cotton, corn, foxtail,barnyard grass, crab grass, field bindweed, pigweed, Wild buckwheat,tomato, and sorghum are scattered on the soil surface and covered withsoil to the pan top.

The soil top is then sprayed with an aliquot of an organic solventcontaining the chemical to be tested. The tests are made at ratesequivalent to 25 pounds per acre and 5 pounds per acre. After spraying,the pans are placed on sand in a bench in a greenhouse, and the bench isflooded with water to /2" above the sand level. The pans of soil arepermitted to absorb moisture through perforations in the pan bottomsuntil the surface is about /2 moist. The excess water is then drainedfrom the bench. The surface of the test pans rapidly becomes completelymoist through capillary action. They are maintained in this condition bysub-irrigation for a two-week period. At the end of said period, thenumber of plants of each species which germinated and grew are counted.

H erbicidesc0ntact or are applied to the plants in a dispersion ofwettable fluidity for spraying. Fourteen days after application of atest compound, the condition of the plants is noted. The quantity ofeach compound utilized is dependent upon the concentration of thecontact dispersion or solution and the rate of application. It isunderstood, of course, that the formulation applied is sufiicient toadequately wet the growing plant and plant parts with an effectiveamount of the active compound. The amount of active compound appliedgenerally ranges from 0.18 pound per acre to 9.0 pounds per acre.

In a representative test, 2-benzyl-4chloro-6-pyrrolidinylmethylphenolshows good activity as a herbicide when applied as a pre-emergent at therate of 25 pounds per acre, and a solution, dispersion, or compoundcontaining 0.5% of 2-benzyl-4-chloro-6-pyrrolidinylmethylphenol showsgood herbicidal contact activity when sprayed on growing plants andplant parts.

F zmgicidef0liage protectant To determine the fungicidal activity, as,for example, against tomato leaf spot caused by Alternuria solani, aselected chemical is dissolved or dispersed in a liquid carrier, such aswater or other suitable liquid. The active ingredient can be in the formof a solution, suspension, dispersion, or emulsion in aqueous ornon-aqueous medium. Desirably 0.01 to 1.0% of a surface active agent byweight is included in the liquid composition. The formulation is sprayapplied to the foliage of four-week-old tomato plants. Twenty-four hourslater, a standardized inoculum, in the form of conidial spores ofAlternaria solani, is sprayed on the tomato plants. The plants are thenincubated for 24-48 hours in a constant temperaturehumidity chamber, andtransferred to a greenhouse where readings are made at appropriatetimes. In a representative test,2-benzyl-4-chloro-G-piperidinylmethylphenol shows good fungicidalactivity against Alternaria solani when applied at a concentration of0.03%, with negligible phytotoxicity toward the tomato plant.

In connection with all of the test data presented, it should be notedthat controls were also run with untreated soil surfaces and unsprayedplants. At the end of the 14-day period, the growth and/ or developmentis observed to determine whether or not development is normal.

Although the compounds of this invention are useful per se as pesticidalagents, it is preferred to apply said compounds to the plant parts and/or the plant-growing medium in a dispersed form with suitable extendingagent. The term dispersion is used herein in its widest sense, meaningthe compound particles may be molecular in size and held in truesolution, or the compound particles may be colloidal in size anddistributed throughout a liquid phase in the form of a suspension oremulsion, or the compound particles may be distributed throughout asolid carrier providing a mixture in particulate form, e.g., pellets,granules, powders, dusts, and the like.

As used herein, the term extending agents connotes any and all of thosesubstances in which the compounds of this invention are dispersed. Itincludes, therefore, the solvents of a true solution, the liquid phaseof suspensions or emulsions, and the solid phase of particulate solids,e.g., pellets, granules, dusts, and powders.

The formulations containing the compounds of this invention, whether inthe form of solids or liquids, for most applications may also include asurface-active agent of the kind sometimes referred to in the art as awetting, dispersing, or emulsifying agent. These agents will be referredto hereinafter more simply as surface-active agents which impart tocompositions the ability to be easily dispersed in an aqueous solution.

The surface-active agents employed can be of the anionic, cationic, ornon-ionic type. The preferred surfaceactive agents are the water-solubleanionic and Watersoluble non-ionic agents. Suitable surface-activeagents are set forth in US. 3,037,904.

The amount or percentage of active ingredient is, of course, added to aformulation in an amount sufiicient to exert the desired pesticidalaction. The amount of formulation utilized varies with the pesticidalactivity of the selected compound, the purpose for which the applicationis being made (i.e., whether for short-term or long-term activity), themanner of application, the particular pesticidal effect desired, andlike variables. If the formulation is to be applied as spray or dust,the percentage of active ingredient can vary from about 0.1% to nearlyby weight of the applied formulation. It must be understood thatdetermination of the proper rate in any given instance is conventionalprocedure to those skilled in the art of pesticidal agents.

In preparing formulations containing the above class of compounds, itmay be preferred to utilize an acid salt rather than the free base. Forexample, the hydrochloride salt of the subject class of compounds isgenerally more soluble in water than the corresponding base compound.Thus, if an aqueous formulation is desirable, the acid salts of thesubject class of compounds can generally be utilized.

While this invention has been described with respect to certain specificembodiments, it is not so limited. It is to be understood thatvariations and modifications thereof may be made without departing fromthe spirit and scope of this invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A method for controlling plant growth comprising applying to soil ata rate of about 0.1 to 25 pounds per acre of a compound having theformula /(CH2)2 R], on CHFN x,

where R is selected from the group consisting of methyl and ethyl, b isan integer from 0 to 2, X is selected from the group consisting ofoxygen, N-CH and CH a is an integer from 0 to 1, and the hydrochloricacid salts thereof.

2. A method for controlling plant growth comprising applying to soil2-benzyl-4-chloro-6-pyrrolidinylmethylphenol at a rate of 0.1 to 25pounds per acre.

3. A method for controlling the growth of fungi comprising applying togrowing plants and plant parts a fungicidally toxic dispersioncontaining from 0.01% to 1.0% of a member selected from the grouconsisting of the compounds having the formula where R is selected fromthe group consisting of methyl and ethyl, b is an integer from 0 to 2, Xis selected from the group consisting of oxygen, NCH and CH a is aninteger from 0 to 1, and the hydrochloric acid salts thereof.

4. A method for controlling the growth of fungi comprising applying togrowing plants and plant parts a fungicidally toxic dispersioncontaining 2-benzyl-4-chloro-6- piperidinylmethylphenol at aconcentration of from 0.01% to 1.0%.

(References on following page) References Cited by the Examiner UNITEDSTATES PATENTS OTHER REFERENCES Wheatley et 211., I. Am. Chem. 500.,vol. 79, pages 747- BrunsOn 260247.7 749 (1957).

Bock 260268 5 McCleary 260-3265 LEWIS GOTTS, Primary Examiner. Binkley16733 X Burckhalter 26O 294-7 X JAMES O. THOMAS, Examiner.

1. A METHOD OF CONTROLLING PLANT GROWTH COMPRISING APPLYING TO SOIL AT ARATE OF ABOUT 0.1 TO 25 POUNDS PER ACRE OF A COMPOUND HAVING THE FORMULA